Venous thromboembolism (VTE), comprising deep venous thrombosis and pulmonary embolism, is a major contributor to morbidity and mortality in the U.S. We propose a 4-year renewal of the Longitudinal Investigation of Thromboembolism Etiology (LITE), a prospective study of VTE in the Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS) cohorts, comprising 21,680 participants followed for more than a decade. We have accomplished much in the previous two project periods, through identification of 548 VTEs and focusing mostly on non-genetic risk factors for VTE. This renewal focuses on identifying new genes for VTE through a genome-wide association study. Our aims are to: (1) Extend VTE event follow-up in ARIC for 2 more years, which is expected to increase the number of LITE VTE events for genotyping by 150. (2) Measure genotypes for 500,000 SNPs spanning the human genome on 468 VTE cases and 936 controls among whites in LITE. (Genotypes in nearly 300 of these subjects will already be done in another study). Rank each SNP by its p-value for a test of association with VTE. (3) Investigate the replicability of the above results by testing the ability of the top 2,600 SNPs from Aim 2 (p<0.005) to significantly predict VTE with the same direction of effect in another case-control study, from the Mayo Clinic (1500 VTE cases and 1500 controls, almost all whites). (4) a. For the significant genes identified in Aim 3, investigate additional SNPs in the LITE and Mayo samples to permit haplotype-based analyses, test gene-gene interactions, and in LITE explore the ability of genotypes to modify the relationship between environmental and lifestyle measures (e.g., obesity, diet) and phenotype (i.e., gene-environment interactions). This aim builds on our findings from previous project periods and will integrate the genetic and non-genetic risk factors for VTE. b. As an exploratory aim, examine whether the significant SNPs and haplotypes in whites are also associated with VTE in African Americans in LITE (n=182 cases and 364 controls). This study is designed to provide new information on genetic risk for VTE, with potential implications for prevention and treatment of VTE. Project Narrative This prospective epidemiologic study is identifying factors that contribute to increased risk of venous thromboembolism, i.e., blood clots in veins that may travel and block blood supply to organs. In this renewal proposal, we seek to identify novel genes that contribute to venous thromboembolism. This will have important implications for the prevention and treatment of this common and significant cardiovascular disease.